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WO2018144481A1 - Copolymères séquencés à plusieurs bras pour systèmes auto-assemblés multifonctionnels - Google Patents

Copolymères séquencés à plusieurs bras pour systèmes auto-assemblés multifonctionnels Download PDF

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Publication number
WO2018144481A1
WO2018144481A1 PCT/US2018/016016 US2018016016W WO2018144481A1 WO 2018144481 A1 WO2018144481 A1 WO 2018144481A1 US 2018016016 W US2018016016 W US 2018016016W WO 2018144481 A1 WO2018144481 A1 WO 2018144481A1
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Prior art keywords
peg
pam
mixture
coating
medical device
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PCT/US2018/016016
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English (en)
Inventor
Tatiana Segura
Nicholas BERNTHAL
Weixian XI
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The Regents Of The University Of California
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Priority to US16/480,864 priority Critical patent/US12208178B2/en
Priority to EP18748384.7A priority patent/EP3577179B1/fr
Publication of WO2018144481A1 publication Critical patent/WO2018144481A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D171/00—Coating compositions based on polyethers obtained by reactions forming an ether link in the main chain; Coating compositions based on derivatives of such polymers
    • C09D171/02—Polyalkylene oxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
    • C08G75/02—Polythioethers
    • C08G75/04—Polythioethers from mercapto compounds or metallic derivatives thereof
    • C08G75/045—Polythioethers from mercapto compounds or metallic derivatives thereof from mercapto compounds and unsaturated compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/12—Copolymers
    • C08G2261/126—Copolymers block
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/05—Polymer mixtures characterised by other features containing polymer components which can react with one another

Definitions

  • the technical field generally relates to the synthesis and use of multi-arm block- copolymers.
  • the technical field relates to multi-arm block-copolymers that utilize polyallyl mercaptan (PAM).
  • PAM polyallyl mercaptan
  • the use of PAM in conjunction with multi-arm poly(ethylene glycol) (PEG) has the ability to generate useful functional, biodegradable coatings that are useful for biomedical implants (e.g., orthopedic and other implants).
  • PMMA polymethylmethacralate
  • PEG-PPS branched poly(ethylene glycol)-poly(propylene sulfide)
  • Factory-coated implants also suffer from the limitation that there is no versatility offered as each coating is loaded with the same antibiotic. This lack of personalization in the coating makeup is important because the physician may want to target a particular bacteria species that may be endemic to the geographical local area or local patient population. Factory- coated implants also may degrade over time limiting the overall shelf life of the implant device.
  • a polymeric delivery platform for the delivery of medicinal or therapeutic compounds such as antibiotics that allows rapid assembly.
  • multi-arm poly(ethylene glycol) (PEG) is reacted with polyallyl mercaptan (PAM) in the presence of a photoinitiator and one or more drugs, medicaments, or pharmaceutical compounds and exposure to an appropriate light source (e.g., ultraviolet or UV light source) to form a PEG-PAM coating of material that may be formed in situ on, for example, one or more surfaces of a medical device.
  • PEG poly(ethylene glycol)
  • PAM polyallyl mercaptan
  • the PEG-PAM coating permits medical devices such as orthopedic implants to remain sterile leaving industry or other storage warehouses and provides surgeons versatility to apply a drug-containing coating on a medical device or on or within the patient directly within the operating room.
  • the drug or medicament includes an antimicrobial agent or drug that can be applied directly to all or part of a medical device.
  • the choice of antimicrobial agent used with the coating may be specifically tailored to the patient's needs.
  • a variety of modalities may be used to apply the drug-containing coating to the medical device surface or a tissue surface of the patient.
  • the coating may be applied as an aerosol such as a spray.
  • the coating may also be applied as a paint using an applicator such as a brush or the like.
  • the coating may also be applied to fill voids or spaces using an injection device such as a syringe.
  • the applied coating is then, in one embodiment, subject to illumination from an appropriate wavelength-emitting light source (e.g., ultraviolet light source).
  • an appropriate wavelength-emitting light source e.g., ultraviolet light source.
  • the multi-arm block-copolymer based system described herein provides a cost-effective, practical alternative to PMMA that biodegrades, has consistent, tailorable release kinetics, and allows patient-specific tailoring of antibiotic loading.
  • the PEG-PAM material described herein may also be used as a coating on or within tissue or an injectable gel.
  • a method of manufacturing or synthesizing PAM includes forming PAM through radial polymerization of 1,3 propanedithiol and allylsulfide along with a photoinitiator such as 2,2-Dimethoxy-2- phenylacetophenone (DMPA).
  • DMPA 2,2-Dimethoxy-2- phenylacetophenone
  • the mixture is then subject to polymerizing ultraviolet light for a period of time to synthesize PAM.
  • the PAM may be thiol-terminated, allyl- terminated or both thiol-terminated and allyl-terminated.
  • a 1 : 1 stoichiometric ratio mixture of 1,3 propanedithiol and allylsulfide generates PAM that is both thiol-terminated and allyl- terminated.
  • a stoichiometric ratio mixture of 1,3 propanedithiol and allylsulfide with a ratio of 1,3 propanedithiol to allylsulfide that is greater than 1 produces PAM that is thiol- terminated.
  • a stoichiometric ratio mixture of 1,3 propanedithiol and allylsulfide with a ratio of 1,3 propanedithiol to allylsulfide that is less than 1 produces PAM that is allyl-terminated.
  • PAM is synthesized by radical polymerization as opposed to anionic polymerization as is the case with PPS.
  • the thiol group of the PAM molecule can be used in various thiol-based click chemistries for polymer modification or functionalization.
  • PAM may be used in conjunction with Michael addition of multi-arm PEG-maleimide in the presence of triethylamine catalyst to synthesize multi-arm-PEG-PAM diblock polymers.
  • eight-arm PEG-maleimide was used to form the multi-arm-PEG-PAM diblock polymer.
  • the molar ratio of PAM may be adjusted to alter the
  • hydrophilicity/hydrophobicity of the synthesized polymer For example, reducing the number of arms reacted with PAM to three (3) from eight (8) makes the block-copolymer water soluble.
  • the allyl group of the PAM molecule can be used to synthesize a PEG-PAM copolymer coating using thiol contained PEG molecules using light activation.
  • multi-arm PEG-thiol molecules can be reacted with PAM in the presence of a photoinitiator and one or more drugs, medicaments, or pharmaceutical compounds under light illumination to form a coating or layer that is applied to one or more surfaces such as the surface of a medical device.
  • a mixture including PEG-thiol, PAM, a photoinitiator, and an antibiotic is applied to a surface of a medical device such as an orthopedic implant.
  • the process of coating one or more surfaces of a medical device and polymerizing the coating may be performed by the surgeon or physician inside a medical operating room.
  • a mixture or solution containing the PEG-thiol, PAM, and photoinitiator may be provided for use by the surgeon or physician.
  • the surgeon or physician may add the desired drug(s), medicament(s), or pharmaceutical compound(s) to this mixture or solution prior to application.
  • the PEG-thiol, PAM, and photoinitiator may already be pre-mixed with the drug(s), medicament(s), or pharmaceutical compound(s).
  • a method of coating one or more surfaces of a medical device includes providing a mixture of polyallyl mercaptan (PAM), a multi-arm
  • PEG poly(ethylene glycol)
  • PEG poly(ethylene glycol)
  • a photoinitiator in an organic solvent containing one or more drugs, medicaments, or pharmaceutical compounds
  • applying the mixture to one or more surfaces of the medical device; and irradiating the mixture with polymerizing light to form a PEG-PAM coating on the one or more surfaces of the medical device containing the one or more drugs, medicaments, or pharmaceutical compounds.
  • a coating material is formed from polymerized polyallyl mercaptan (PAM) and a multi-arm poly(ethylene glycol) (PEG), wherein the coating material contains one or more drugs, medicaments, or pharmaceutical compounds therein.
  • the coating material in one embodiment, is disposed on one or more surfaces of a medical device.
  • the one or more drugs, medicaments, or pharmaceutical compounds includes one or more antibiotics.
  • the coating material may be applied in one or more layers.
  • a method of making PEG-PAM copolymer containing a drug or pharmaceutical compound therein includes providing a mixture of polyallyl mercaptan (PAM), a multi-arm poly(ethylene glycol) (PEG), and a photoinitiator in an organic solvent containing one or more drugs, medicaments, or pharmaceutical compounds.
  • the mixture is applied to the surface of a substrate such as a surface (or multiple surfaces) of a medical device or implant and the applied mixture is illuminated with polymerizing light.
  • a method of making PEG-PAM copolymer includes providing a mixture of polyallyl mercaptan (PAM) and a multi-arm poly(ethylene glycol) (PEG) in an organic solvent and adding a catalytic amount of trimethylamine.
  • PAM polyallyl mercaptan
  • PEG poly(ethylene glycol)
  • a method of making polyallyl mercaptan includes providing a mixture containing 1,3 propanedithiol and allylsulfide in the presence of a photoinitiator and illuminating the mixture with ultraviolet light.
  • FIG. 1 illustrates the synthesis of PAM according to one embodiment from the radial polymerization of 1,3 propanedithiol and allylsulfide.
  • the stoichiometric ratio of allylsulfide to 1,3 propanedithiol may be adjusted to control whether the terminal ends of the PAM are thiol groups, allyl groups, or both.
  • FIG. 2 illustrates the synthesis of PEG-PAM using a multi-arm PEG-maleimide and PAM in the presence of triethylamine (TEA) catalyst according to one embodiment.
  • TAA triethylamine
  • FIG. 3 illustrates a schematic representation of multi-arm PEG-PAM amphiphilic diblock polymer formed using different ratios of thiol to PEG-maleimide.
  • the graph illustrates reversible shear- thinning behavior.
  • Rheology measurement PEG-PAM hydrogels were allowed to self- assemble for 30 min before transferred to an 8 mm plate-to-plate rheometer (Physica MCR 301, Anton Paar, Ashland, VA). An evaporation blocker system was used during measurements. For frequency sweep, the data were collected for the modulus with a frequency range of 0.1-100 rad/s under a 1% constrain at 37 °C.
  • FIG. 5 A illustrates FT-IR spectra of PAM and the oxidized forms.
  • FT-IR spectra was collected by Jasco 420 FTIR Spectrophotometer.
  • the sample pellet was prepared by mixing the 10 mg polymer and 500mg KBr.
  • GPC/LS Gel permeation chromatography /light scattering
  • LS Wyatt DAWN EOS light scattering
  • RI Optilab rEX refractive index
  • FIG. 5B illustrates the rheometry measurement of storage modulus and loss modulus of PEG-PAM before and after H2O2 treatment.
  • FIG. 6A illustrates the synthesis of PEG-PAM copolymer using an eight arm PEG- thiol, a photoinitiator (e.g., DMPA), and PAM. UV light is used to polymerize the mixture.
  • a photoinitiator e.g., DMPA
  • PAM photoinitiator
  • FIG. 6B schematically illustrates the formation of PEG-PAM copolymer on a medical device or implant containing a drug, medicament, or pharmaceutical compound therein using multi-arm PEG-thiol, a photoinitiator, and PAM. Ultraviolet light is used to polymerize the mixture.
  • FIG. 7 illustrates a process for applying or forming a PEG-PAM coating on medical device or implant according to one embodiment.
  • FIG. 8A illustrates scanning electron microscopic (SEM) images of the surfaces of a bare titanium pin (8-mm in diameter).
  • FIG. 8B illustrates a SEM image of a titanium pin coated with PEG-PAM containing vancomycin.
  • FIG. 9 illustrates a graph of the in vitro passive release (concentration/area) of a single layer of vancomycin containing PEG-PAM coated on the titanium pins. Quantified via
  • UV-Vis the daily release of vancomycin per pin over 14 days.
  • FIG. 10 illustrates postoperative in vivo S. aureus bioluminescence signals
  • FIG. 11 illustrates a graph of bioluminescence as a function of time for the pin with no coating, pin with PEG-PAM, and pin with PEG-PAM loaded with vancomycin.
  • FIG. 12 illustrates a graph of colony -forming unit (CFU) enumeration from implants and peri-implant tissue for implants with no coatings PEG-PAM coating (no drug), and PG-PAM (with vancomycin).
  • CFU colony -forming unit
  • FIG. 13 illustrates a graph showing the release profile (release/area) from three (3) layers of PEG-PAM coating on a titanium K-wire implant.
  • FIG. 14 illustrates a graph of the thickness of a single layer and multiple layers deposited on a K-wire implant. Data is shown for a single layer, three layers, five layers, and eight layers.
  • FIG. 15 is a graph showing the loading of vancomycin for coatings having a single layer, three layers, five layers, and eight layers.
  • FIG. 16 is a graph showing the cumulative release percentage of vancomycin from a single layer of vancomycin-containing PEG-PAM coated on a titanium pin.
  • FIG. 17 illustrates the quantification of the diameters of the inhibition zones for the non-coated pin, the pin coated with PEG-PAM only, and the pin coated with PEG-PAM and vancomycin.
  • FIG. 19 illustrates the quantification of the diameters of the inhibition zones for a non-coated pin (control) and a pin coated with PEG-PAM loaded with Tobra against Pseudomonas (PAOl strain).
  • FIG. 20 illustrates the quantification of the diameters of the inhibition zones for a non-coated pin (control) and a pin coated with PEG-PAM, piperacillin and Tazobacta against
  • FIG. 21 illustrates lateral radiographs of titanium implants containing no coating, PEG-PAM (no drug), and PEG-PAM loaded with vancomycin.
  • POD stands for postoperative days.
  • FIG. 22 illustrates the post-operative in vivo bioluminescence analysis of titanium pins implanted into the femur of a mouse. Specifically, a graph of in vivo bioluminescence (mean maximum flus) of S. Aureus is shown as a function of time (PODs).
  • FIG. 23 illustrates the post-operative in vivo bioluminescence analysis of various diameter titanium pins implanted into the femur of a mouse.
  • FIG. 24 schematically illustrates the synthesis of a PEG-PAM diallyl (PEG- PAMDA) coating according to one embodiment.
  • the coating is formed on an L-shaped stainless steel medical device or implant for use in spinal applications.
  • FIG. 25 illustrates the in vitro release of vancomycin from an L-shaped stainless steel pin having a single layer of PEG-PAM. Also illustrated in the in vitro release of vancomycin from an L-shaped stainless steel pin having three layers of PEG-PAMDA.
  • FIG. 26 illustrates the post-operative in vivo analysis of 0.1 mm sized stainless steel L-shaped implants that were implanted in the vertebrae of a mouse.
  • the implants had either PEG-PAMDA (3 layers) and no drug or PEG-PAMDA (3 layers) and vancomycin.
  • FIG. 27 illustrates a graph of cumulative release of vancomycin as a function of time for PEG-PAM crosslinked with dithiol containing polymers to convert the coating into chemically crosslinked hydrogel.
  • FIG. 28 illustrates a graph of cumulative release of Alex-488 from PEG-PAM hydrogel functionalized with MMP -Alex-488. The presence of collagenase dramatically increases the rate of release.
  • a polymeric delivery platform is disclosed that is formed from a PEG-PAM copolymer of polyallyl mercaptan (PAM) and a multi-arm poly(ethylene glycol).
  • the PEG-PAM copolymer system may be used for the delivery of medicinal or therapeutic compounds such as antibiotics to living tissue.
  • the polymeric delivery platform in one embodiment, is coated in situ on one or more surfaces of a medical device or implant that is to be used in a mammalian subject. In other embodiments, the polymeric delivery platform may be directly delivered to tissue or tissue regions of a mammalian subject.
  • a multi-arm poly(ethylene glycol) (PEG) is reacted with polyallyl mercaptan (PAM) in the presence of an initiator compound (e.g., photoinitiator) and one or more drugs, medicaments, or pharmaceutical compounds.
  • an initiator compound e.g., photoinitiator
  • the mixture is exposed to an initiator source such as light, heat, or a redox initiator to polymerize the copolymer.
  • the initiator compound is a photoinitiator and the mixture is first applied to one or more surfaces of a medical device or implant and is then exposed to an appropriate polymerizing light source (e.g., ultraviolet light source or visible light source) to form a PEG-PAM copolymer coating or layer(s) that is formed in situ on the medical device or implant.
  • an appropriate polymerizing light source e.g., ultraviolet light source or visible light source
  • the PEG-PAM coating permits medical devices or implants to remain in a sterile state prior to use and provides surgeons the versatility to customize the drug, medicament, or pharmaceutical compound-containing coating on a medical device or implant (or applied on or within the patient directly within the operating room in other applications).
  • the drug, medicament, or pharmaceutical compound includes one or more antimicrobial agents or drugs that can be applied directly to all or part of a medical device or implant.
  • the choice of antimicrobial agent used with the PEG-PAM coating may be specifically tailored to the patient's needs.
  • the PEG-PAM coating described herein uses PAM as one of the copolymer blocks.
  • PAM was previously known to be created by thiol-ene click polyaddition of ⁇ , ⁇ - alkylene thiols, for example, as described in Deubel et al, Polythioethers by Thiol-Ene Click Polyaddition of ⁇ , ⁇ -Alkylene Thiols, Macromol. Rapid Commun., 34, 1020-1025 (2013).
  • this synthesis process is a multi-step process that takes a considerable amount of time.
  • a new method of synthesizing PAM is disclosed. FIG.
  • the polymerization may be performed under 365nm UV light irradiation with the presence of a photoinitiator and, depending on the relative stoichiometric ratio of 1,3 propanedithiol and allylsulfide produces PAM that is either thiol terminated, allyl terminated, or thiol and allyl terminated.
  • PAM is formed that has ends that are both thiol and allyl terminated.
  • DMPA 2,2-Dimethoxy-2- phenylacetophenone
  • PEG-PAM may be synthesized using the PAM described above in one of two synthesis methods.
  • PAM n between 5 and 30
  • PEG-PAM conjugated with multi-arm PEG through any number of thiol reactive groups on the PEG molecule using a catalytic amount of base catalyst such as triethylamine (TEA).
  • the reactive groups on PEG usable with this synthesis method include by way of example, PEG-acrylate, PEG- vinylsulfone, PEG-maleimide, PEG-acrylamide, PEG-isocyanate, PEG-bromide, and PEG- epoxide.
  • PEG-PAM copolymer material using the multi-arm PEG-maleimide (e.g., eight arm) and PAM (n between 5 and 30) in the presence of triethylamine (TEA) catalyst.
  • TAA triethylamine
  • Any number of arms of for the multi-arm PEG may be used.
  • Commercially available PEG with three (3), four (4), five (5), six (6), seven(7), eight(8) or more arms are available and usable with the synthesis method described herein.
  • PAM and the 8-Arm-PEG maleimide were dissolved in deuterated chloroform (CDCI 3 ) and a catalytic amount of triethylamine was added into the mixture and then stirred for 3 hours. The solvent was removed under vacuum and the crude product was precipitated in cold ether (4 °C).
  • the thiol end group of PAM can be used in various thiol based click chemistries for polymer modification or functionalization.
  • thiol- maleimide was used for Michael addition to synthesize multi-Arm-PEG-PAM diblock polymers both starting from 8-Arm-PEG-maleimide (Mw: 40,000).
  • the fully functionalized block polymer (8-Arm-PEG-PEG) was dissolved in the CDCI 3 (10 wt%) and instantly formed organogel, which is not soluble in water. If instead of reacting the eight (8) arms of the PEG with PAM, one only reacts three (3) arms, which would decrease the percentage of hydrophobic in the structure; the polymer is then water soluble.
  • the PAM with between three and five arms of the 8-Arm-PEG-maleimide as seen in FIG. 3.
  • the degree to which PAM reacts with the arms of the PEG-maleimide structure may be controlled by the molar ratio of PAM to PEG-maleimide with a larger amount of PAM being used to react with a higher number of arms while a lower amount of PAM yields to fewer arms being occupied.
  • the PEG-PAM copolymer is soluble in water at 5 wt% for stable hydrogel formation. Because the gelation mechanism is based on the hydrophobic interaction between PAM parts of the copolymer, it is expected to exhibit shear-thinning behavior like other supermolecular hydrogels such as PEG-PPS. Small amplitude oscillatory shear rheometry was performed to demonstrate the supermolecular interactions in PEG-PAM hydrogel. Strain sweeps at a constant oscillatory frequency of 6.5 rad/s at 25 °C revealed that the hydrogel could be disrupted under high strain condition.
  • FT-IR FT-IR was used to demonstrate the chemical transformation of thio-ether to sulfone/sulfoxide by monitoring the appearance of special peaks after H2O2 oxidation as seen in FIG. 5A.
  • polythioether P2 0.5 g was dissolved in chloroform (50 mL) at 64 °C. Subsequently 30% hydrogen peroxide solution (0.5 mL) was added to the reaction flask. After 2 h of reaction, the formed polymer was precipitated in a cold ether and dry in a vacuum oven at 50 °C.
  • FIG. 5B illustrates the rheometry measurement of storage modulus and loss modulus of PEG-P AM before and after H2O2 treatment.
  • PEG-P AM copolymer could be disrupted by oxidative species
  • PEG- PAM polymer was further investigated as a coating material for use with medical devices and implants and in particular for orthopedic implants that would controllably release antibiotics or other drugs from the PEG-P AM polymer network.
  • another separate light polymerization-based synthesis method was investigated for the ability to polymerize PEG- PAM polymer directly on one or more surfaces of a medical device or implant. This second method of synthesizing PEG-P AM is used to form a coating on a substrate such as a medical device or implant (or even tissue).
  • the coating is formed by polymerizing a mixture containing polyallyl mercaptan (PAM), a multi-arm poly(ethylene glycol) (PEG), an initiator, and one or more drugs, medicaments, or pharmaceutical compounds. Any number of arms of for the multi-arm PEG may be used. Commercially available PEG with three (3), four (4), five (5), six (6), seven(7), eight(8) or more arms are available and usable with the synthesis method described herein.
  • polymerization is initiated in response to applied stimulus that works in conjunction with the initiator.
  • the initiator may include a UV sensitive initiator such as DMPA and the mixture is polymerized by exposing the mixture to UV light.
  • the initiator may include a visible light sensitive initiator such as Irgacure 2959® (which can also be used for UV light).
  • a thermal initiator may be used such as azobisisobutyronitrile (AIBN).
  • a redox initiator may be used such as ammonium persulfate (APS)/N,N,N ,N - tetramethylethylenediamine (TMEDA).
  • the initiator is a photoinitiator.
  • FIG. 6A illustrates one embodiment of the synthesis of PEG-P AM using a four- arm PEG.
  • the mixture is subject to UV light to form PEG-PAM having a chemical formula (C2H 4 0) m S4[C3H 6 S]n.
  • the reactive groups on PEG usable with this synthesis method include by way of example, PEG-acrylate, PEG-vinylsulfone, PEG-maleimide, PEG-acrylamide, PEG-epoxide, PEG-thiol, PEG-norborene, PEG-vinyl, PEG-allyl, and PEG-alkyne.
  • an initiator such as DMPA is used along with UV light to form the PEG-PAM copolymer from PEG and PAM as well as the drug, medicament, or pharmaceutical compound (which is omitted from FIG. 6A) and an organic solvent.
  • FIG. 6B schematically illustrates one embodiment of a method of coating one or more surfaces of a medical device or implant 10.
  • the medical device or implant 10 may include, by way of illustration and not limitation, an orthopedic implant, a spinal implant, ajoint replacement device, pacemakers, insulin pumps, surgical pins, screws, or other surgical hardware.
  • the coating is applied to a metallic surface of the medical device or implant 10 such as titanium or stainless steel but it should be appreciated that the coating and method of use is not limited to the particular composition of the substrate on which the coating resides. For example, it may also be applied to polymer or ceramic surfaces. In the particular example of FIG.
  • PAM and a four-arm PEG-SH are mixed with a drug, medicament, or pharmaceutical component along with a small amount of organic solvent such as chloroform.
  • organic solvents that may be used include dichloromethane (DCM), chloroform, and dimethyl sulfide (DMS).
  • the amount of organic solvent may vary but is typically under 10 % weight basis (e.g., 6% by weight).
  • the drug that is incorporated into the PEG-PAM coating is the antibiotic vancomycin.
  • the drugs, medicaments, or pharmaceutical compounds may be loaded within the PEG-PAM coating. Because of the use of the organic solvent, the drugs, medicaments, or pharmaceutical compounds should generally be dissolvable or soluble is organic solvents. It should also be appreciated that more than one type of drug, medicament, or pharmaceutical compounds may be carried by the coating or gel formed by the methods described herein.
  • the surgeon or physician is provided with or assembles the mixture of PEG, PAM, initiator, organic solvent, and the drug, medicament, or pharmaceutical compound.
  • the relative amounts of PEG and PAM in the mixture depends on the type of PEG used and the number of arms that are intended to be occupied. For example, for a four-arm PEG molecule, there typically would be PAM in a 4x (molar basis) so that all the PEG arms are bound to PAM.
  • the amount of drug, medicament, or pharmaceutical compound that is added may vary.
  • a typical concentration of the drug, medicament, or pharmaceutical compound is generally within or below about 10-20 mg/mL of mixture of PEG and PAM.
  • This mixture may be added to a delivery device such as spray bottle 12 or the like that can be used to spray a coating onto the medical device or implant 10 (other applicators such as an air-brush type applicator may also be used).
  • the spray bottle 12 may actuated to apply a generally uniform coating of the mixture onto one or more surfaces of the medical device or implant 10 as seen in operation 1000 of FIG. 7.
  • medical device or implant 10 may be coated with the mixture including PEG, PAM, initiator, and drug with an applicator 14 such as a brush.
  • the medical device or implant 10 may be dipped into the mixture and removed.
  • the medical device or implant 10 is irradiated with light from a light source 16 (e.g., visible or UV light depending on the initiator) to polymerize the PEG-PAM polymer directly on one or more surfaces of the medical device or implant 10.
  • the light source 16 may include a light, gun, wand, or other device that is typically found in hospitals and other medical settings and is used to illuminate a surface with light.
  • the coating is illuminated for a short period of time (e.g., less than 5 minutes) to properly form the PEG-PAM copolymer. After applying the coating to the medical device or implant 10 some amount of time may elapse to enable the solvent to evaporate prior to illumination. This optional waiting period may last a few minutes. Thus, polymerization takes place in situ on the surface of the medical device or implant 10.
  • multiple layers may optionally be coated on the surface of the medical device or implant 10 as seen by operation 1050.
  • the mixture is applied and then subject to irradiation followed by application of another layer of the mixture followed by irradiation. This can proceed for a number of cycles to create the desired thickness or number of layers on the medical device or implant 10.
  • only a portion of the surface of the medical device or implant 10 is coated.
  • the coating system described herein may be used with any number of medical devices or implants 10 but has particular suitability to joint replacement devices.
  • the coating system may be used also with orthopedic trauma implants or spinal implants.
  • Other implantable medical devices may also be coated such as pacemakers, insulin pumps, and the like.
  • the surfaces that are coated are typically metal such as titanium, stainless steel, cobalt-chrome although other materials may also be coated. These include plastics, ceramics, as well as allograft cadaver bone.
  • the initiator is a photoinitiator which requires activation by light. It should be understood that in other embodiments, a heat applicator may be used to apply heat when the initiator is a thermal initiator. In other embodiments, for example, where the initiator is a redox initiator, there may be no need for a separate stimulation device. The process from start to finish is may be accomplished relatively quickly, for example, under 10 minutes (e.g., around 5 minutes) depending on the number and size of surfaces to be coated. Finally, as seen in operation 1200, the medical device or implant 10 is implanted in the subject.
  • PEG-PAM polymers loaded with antibiotic were coated on the surface of titanium pins (i.e., K-wires) through in situ UV coating as described above which greatly reduced the amount to time compared with traditional methods.
  • antibiotic vancomycin
  • 4-arm PEG-thiol and PAM polymers were dissolved in dichloromethane (DCM) to make 6 % (w/v) solution, which was used to dissolve vancomycin at concentration of 20 mg/ml.
  • DCM dichloromethane
  • the K-wires were submerged in the antibiotic- encapsulated polymer solution 1 min and later taken out allowing evaporation of DCM.
  • FIG. 8A illustrates scanning electron microscopic (SEM) images of the surfaces of a bare titanium pin (8-mm in diameter) and FIG. 8B illustrates a SEM image of a titanium pin coated with PEG- PAM containing vancomycin.
  • the coating thickness is ⁇ 2 ⁇ which is an inconsequential amount for press fit implants.
  • FIG. 9 illustrates a graph of the in vitro passive release of a single layer of vancomycin containing PEG-PAM coated on the titanium pins.
  • the daily release results indicated the concentration of vancomycin maintained above the minimum inhibition concentration (MIC) for 14 days.
  • the PEG-PAM coated pins were subject to an in vivo assay to measure their antibacterial efficacy.
  • the in vivo assay employed bioluminescent
  • Staphylococcus aureus Xen36 strain that naturally produces a blue-green light emitted only by metabolically active bacteria as an "indicator" that reflects bacterial infections.
  • Uncoated pins, coated pins with PEG-PAM and coated pins with PEG-PAM containing vancomycin were implanted into the femoral intramedullary canal of a mouse in a retrograde fashion and inoculated with the S. Aureus. The results from monitoring the bioluminescent signal indicated the vancomycin containing PEG-PAM pins has significantly lower signal comparing with other two groups within 21 days after implantation as seen in FIG. 10.
  • FIG. 13 illustrates the release profile from three (3) layers of PEG-PAM coating on a titanium K-wire implant.
  • PEG-PAM coatings increases with the number of coating layers that are applied to the medical device or implant 10.
  • FIG. 14 illustrates the thickness of the resultant layer(s) on a K-wire implant for a single layer, three layers, five layers, and eight layers. A general linear relationship exists between the number of layers and the total thickness of the applied coating.
  • FIG. 15 illustrates that by increasing the number of layers of PEG-PAM coating, the loading of a drug, medicament, or pharmaceutical compound (in this example vancomycin) is increased.
  • FIG. 16 illustrates a graph showing the cumulative release of vancomycin from a single layer of vancomycin- containing PEG-PAM coated on a titanium pin. As seen in FIG. 16 after about 3 days most of the vancomycin was released. In this experiment, the vancomycin was released relatively quickly.
  • Titanium pins that were bare (not coated), coated with PEG-PAM only, and coated with PEG-PMA and vancomycin were tested for their ability to inhibit the growth of S. Aureus.
  • the respective pins were placed in in a petri dish containing growth media and seeded with S. Aureus. After 3 days the petri dishes containing the respective coated/non- coated pins were examined for inhibited bacterial growth which could be visualized as a zone or region around the respective pins where bacteria did not grow.
  • the pin containing PEG- PMA and vancomycin showed a clear and marked zone without bacterial growth whereas the other two pins with no coating or PEG-PAM only did not show any sort of similar inhibition zone.
  • FIG. 17 illustrates the quantification of the diameters of the inhibition zones for the non-coated pin, the pin coated with PEG-PAM only, and the pin coated with PEG-PAM and vancomycin.
  • FIG. 19 illustrates the quantification of the diameters of the inhibition zones for a non-coated pin (control) and a pin coated with PEG-PAM loaded with Tobra against Pseudomonas (PAOl strain) using similar testing procedure as described above with respect to FIG. 17.
  • FIG. 20 illustrates the quantification of the diameters of the inhibition zones for a non-coated pin (control) and a pin coated with PEG-PAM, piperacillin and Tazobacta against E. Coli using similar testing procedure as described above with respect to FIG. 17.
  • Periprosthetic osteolysis is a serious complication in orthopedic implants, including, for example, total hip replacement (THR) surgery. Osteolysis can lead to prosthesis loosening and periprosthetic fracture. These complications cause significant morbidity and often require additional surgical intervention.
  • THR total hip replacement
  • a titanium pin was implanted into the femur of a mouse. Three different types of pins were implanted: a non- coated implant, an implant coated with PEG-PAM (no drug), and an implant coated with PEG-PAM and vancomycin. As seen in FIG.
  • FIG. 22 illustrates the post-operative in vivo bioluminescence analysis of titanium pins implanted into the femur of a mouse. The pins that were implanted had PEG-PAM (no drug), PEG-PAM loaded with rifampin, and PEG-PAM loaded with rifampin and
  • vancomycin After implantation of the pins, the top, exposed part of the implant was inoculated with S. aureus and was analyzed using the IVIS® Spectrum (PerkinElmer ) in vivo imaging system. Higher signal levels correspond to high or progressed infection post- surgery. As seen in FIG. 22, both the rifampin and rifampin/vancomycin loaded pins maintain the signal at around baseline which indicates that it clears the injections coming from the bacterial challenge.
  • FIG. 23 illustrates the post-operative in vivo analysis of various sized stainless steel pins implanted into the femur of a mouse.
  • the pins that where implanted including a control pin (no coating) as well as various diameter pins (0.1 mm, 0.6 mm, 0.8 mm) coated with PEG-PAM loaded vancomycin.
  • the top, exposed part of the implant was inoculated with S. aureus and was analyzed using the IVIS® Spectrum as described above. Higher signal levels correspond to high or progressed infection post- surgery.
  • the PEG-PAM + vancomycin group of pins maintains the measured bioluminescence signal at or near baseline levels.
  • FIG. 24 schematically illustrates the synthesis of PEG-PAM diallyl (PEG- PAMDA) coatings according to one embodiment.
  • the PAM that is used to form the PEG-PAMDA includes two allyl terminal ends, i.e., PAM diallyl or PAMDA.
  • PAM diallyl or PAMDA a four arm PEG-thiol molecule was used in conjunction with PAMDA and the drug vancomycin to coat an L-shaped stainless steel pin that was used for spinal surgery. Any number of arms of for the multi-arm PEG may be used.
  • Commercially available PEG with three (3), four (4), five (5), six (6), seven(7), eight(8) or more arms are available and usable with the synthesis method described herein.
  • FIG. 25 illustrates the in vitro release of vancomycin from an L-shaped stainless steel pin having a single layer of PEG-PAM.
  • vancomycin is released much more slowly with the chemically crosslinked PEG-PAMDA coating.
  • chemical crosslinking of the coating may be employed to control the time release of the drug, medicament, or pharmaceutical compound.
  • FIG. 26 illustrates the post-operative in vivo analysis of 0.1 mm sized stainless steel L-shaped implants that were implanted in the vertebrae of a mouse.
  • the implants that where implanted and tested for in vivo bioluminescence included an implant coated with three layers of PEG-PAMDA (with no drug) and another implant coated with three layers of PEG-PAMDA and also loaded with vancomycin. After implantation, exposed part of the implant was inoculated with S. aureus and was analyzed using the IVIS® Spectrum through 25 days. As seen in FIG. 26, the implant coated with PEG-PAMDA loaded with vancomycin maintained the bioluminescent signal at around baseline levels. Thus, the drug loaded implant was able to clear infections coming from this bacterial challenge.
  • PEG-PAM hydrogel was assembled by hydrophobic interaction and it was a physical crosslinked hydrogel whose stability was affected by various external stimulus.
  • the stability of PEG-PAM hydrogel can be easily tuned through incorporation of chemical crosslinker. Because the terminals of PEG- PAM are allyl group which is a typical substrate for thiol-ene crosslinking, difunctional thiol molecules were employed in the chemical crosslinking reaction to achieve the transformation of physically crosslinked PEG-PAM hydrogel to chemically crosslinked PEG-PAM hydrogel.
  • PEG-PAM could be crosslinked with dithiol containing polymers to convert the coating into chemically crosslinked hydrogel, which would lead to decreased diffusion ability of antibiotics inside of the hydrogel.
  • PEG-PAM is produced using the first synthesis method described herein, namely, PAM is conjugated with PEG through a thiol reactive groups on the PEG molecule using a catalytic amount of base catalyst such as triethylamine (TEA).
  • TAA triethylamine
  • PEG-PAM is then hydrated and PEG-dithiol is added along with the drug (e.g., vancomycin) and photoinitiator (e.g., lithium phenyl-2,4,6-trimethylbenzoylphosphinate(LAP)) were mixed together and 365nm UV light was used to trigger the crosslinking reaction.
  • the drug e.g., vancomycin
  • photoinitiator e.g., lithium phenyl-2,4,6-trimethylbenzoylphosphinate(LAP)
  • HS-MMP-peptide-Alexa488 was incubated with 4-arm PEG-PAM and exposed to UV light to induce attachment of the peptide to the vinyl groups in PAM.
  • the hydrogel was allowed to form through physical interactions.
  • the incubation of the gel in collagenase led to rapid release, achieving -60% cumulative release in one day.
  • less than 10% release was observed in the absence of collagenase at the same one day time period.
  • the addition of protease degradable peptides to the PEG-PAM coating may be used to accelerate the release of drugs, medicaments, or pharmaceuticals from the PEG-PAM coating.
  • the eluting properties of the PEG-PAM coating can be adjusted or tuned depending on the desired properties of the coated device or implant.
  • the drug, medicament, or pharmaceutical may be eluted in a linear fashion over time (this may be a slow release or a rapid release).
  • an increase or spike in elution may be desired either right after implantation or several days or weeks after implementation.
  • the PEG-PAM elution kinetics may be modified for the appropriate application.

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Abstract

La présente invention concerne un matériau copolymère de poly(éthylène glycol)-polyallyl mercaptan (PEG-PAM) utilisé en tant que revêtement contenant un médicament pour des implants médicaux. Selon un mode de réalisation, un mélange de poly(éthylène glycol) (PEG) multi-bras, de polyallyl mercaptan (PAM), d'un photoinitiateur, d'un solvant organique et d'un ou de plusieurs médicaments, de médicaments, ou de composés pharmaceutiques, est appliqué sur une surface de l'implant et est exposé à une source de lumière de polymérisation pour former un revêtement de matériau PEG-PAM qui est formé in situ sur l'implant. Le revêtement de PEG-PAM peut être utilisé par des chirurgiens pour incorporer des médicaments antibactériens ou analogues dans des revêtements qui sont appliqués, dans un contexte de salle d'opération, à des dispositifs médicaux tels que des implants orthopédiques. Le type de médicament et le dosage peuvent être personnalisés pendant l'opération de revêtement et adaptés aux besoins du patient. Le PEG-PAM peut également être appliqué sous la forme d'un revêtement sur un tissu ou à l'intérieur de ce dernier, ou sous la forme d'un gel injectable.
PCT/US2018/016016 2017-01-31 2018-01-30 Copolymères séquencés à plusieurs bras pour systèmes auto-assemblés multifonctionnels WO2018144481A1 (fr)

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US12208178B2 (en) 2025-01-28

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